Inhibition of endotoxin-induced TNF-α production in macrophages by 5Z-7- oxo-zeaenol and other fungal resorcylic acid lactones

Abstract

Resorcylic acid lactones are fungal metabolites that exhibit a wide range of biological properties which includes oestrogenic, antifungal, phytotoxic and anti-inflammatory activity. The capacity of 5Z-7- oxo-zeaenol, a resorcylic lactone of fungal origin and six naturally occurring analogues to inhibit lipopolysaccharide (LPS)-induced cytokine production in phorbol 12-myristate-13-acetate (PMA)-treated cultured myelomonocytic cells (U937) was compared. The activity of the natural analogues in the U937 assay varied over 10 4-fold, with 5Z-7- oxo-zeaenol the most potent of those tested inhibiting tumour necrosis factor-alpha (TNFα) production in these cells with IC 50 of 6 nM. The isomeric 7- oxo-zeaenol and structurally more distant monorden (radicicol) were the next most active compounds with IC 50 ∼500 nM, and zearalenone, the least active with IC 50>400 μM. 5Z-7- oxo-zeaenol retained activity in LPS-stimulated peripheral blood mononuclear cells with an IC 50 of 10–25 nM. This compound also inhibited LPS-induced TNFα production in whole blood experiments (IC 50 100–1000 nM) and lowered serum levels of TNFα in mice when administered prior to LPS. 5Z-7- oxo-zeaenol was shown to inhibit the phosphorylation and activation of mitogen-activated protein kinase (MAPK) induced by LPS. These data are consistent with a mechanism of action at or upstream of MAPK with resultant downstream effects. This series of naturally occurring analogues represents an interesting group of compounds with diverse biological properties. Of this series, 5Z-7- oxo-zeanenol has exceptionally potent anti-inflammatory properties exhibited by its strong inhibition of cytokine production.